β3 adrenergic agonists

ABSTRACT

The present invention relates to 2-imidazo[1,2-a]pyridine group containing β 3  adrenergic receptor agonists or pharmaceutical salts thereof.

This application is a divisional under 35 U.S.C. Section 121 of U.S.patent application Ser. No. 10/495,133, filed May 7, 2004, now U.S. Pat.7,071,208 B2, which is a national phase application under 35 U.S.C.Section 371 for PCT/US02/33625, filed Nov. 12, 2002, which claims thebenefit under 35 U.S.C. Section 119(e) of U.S. provisional patentapplication 60/334,031, filed Nov. 20, 2001.

The current preferred treatment for Type 2, non-insulin dependentdiabetes as well as obesity is diet and exercise, with a view towardweight reduction and improved insulin sensitivity. Patient compliance,however, is usually poor. The problem is compounded by the fact thatthere are currently no approved medications that adequately treat bothType 2 diabetes or obesity.

One therapeutic opportunity that has recently been recognized involvesthe relationship between adrenergic receptor stimulation andanti-hyperglycemic effects. Compounds that act as β₃ receptor agonistshave been shown to exhibit a marked effect on lipolysis, thermogenesisand serum glucose levels in animal models of Type 2 (non-insulindependent) diabetes. The β₃ receptor, which is found in several types ofhuman tissue including human fat tissue, has roughly 50% homology to theβ₁ and β₂ receptor subtypes yet is considerably less abundant.Stimulation of the β₁ and β₂ receptors can cause adverse effects such astachycardia, arrhythmia, or tremors. An agonist that is selective forthe β₃ receptor over the β₁ and β₂ receptors is, therefore, moredesirable for treating Type 2 diabetes or obesity relative to anon-selective agonist.

However, recent studies have suggested the presence of an atypical βreceptor associated with atrial tachycardia in rats (Br. J. ofPharmacol., 118:2085-2098, 1996). In other words, compounds that are notagonists of the β₁ and β₂ receptors can still modulate tachycardiathrough activation of a yet to be discovered β₄ or through some otherunknown pathway.

U.S. Pat. No. 5,001,132 discloses certainN-([imidazo[1,2-a]pyridinyl]ethyl)-1-phenoxypropan-2-ol amines astherapeutics for the treatment of glaucoma, i.e., said compounds arebeta-blocking agents.

A large number of more recent publications have appeared in recent yearsreporting success in discovery of agents that stimulate the β₃ receptor.Despite these recent developments, there remains a need to develop aselective β₃ receptor agonist which has minimal agonist activity againstthe β₁ and β₂ receptors.

The present invention relates to a compound of formula I:

wherein:

m is 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

A¹, A² and A³ are carbon or nitrogen provided that only one of A¹, A²and A³ can be nitrogen;

each D is either carbon or nitrogen provided that at least one D must benitrogen;

each D′ is either carbon or nitrogen provided that only one D′ can benitrogen;

and further provided that the total number of D and D′ that are nitrogenmust be two and only two;

Het is an optionally substituted, optionally benzofused 5 or 6 memberedheterocyclic ring;

R¹ and R² are independently H, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₄ haloalkyl, or SO₂(C₁-C₆ alkyl);

R³ is H or C₁-C₆ alkyl;

R⁴ and R⁵ are independently at each occurrence H or C₁-C₆ alkyl; or R⁴and R⁵ combine with the carbon to which they are both attached to form aC₃-C₇ carbocyclic ring;

R⁶ is independently at each occurrence halo, hydroxy, cyano, C₁-C₆alkyl, C₁-C₄ haloalkyl or C₁-C₆ alkoxy;

R⁷ is H, CO₂R⁸, CONR⁸R⁸, CH═CHR⁹, CH₂CH₂R⁹, NR⁸R⁸, NR⁸SO₂R⁸,O(CR¹⁰R¹¹)_(p)R¹², O(CR¹⁰R¹¹)_(q)R¹³, SO₂R⁸, SO₂NR⁸R⁸, optionallysubstituted phenyl or optionally substituted heterocycle;

X is absent or is OCH₂ or SCH₂;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

R⁸ is independently at each occurrence H, C₁-C₆ alkyl or phenyl; or whentwo R⁸ moieties are connected to the same nitrogen atom, then said R⁸moieties may combine with the nitrogen to which they are attached toform a pyrollidinyl, piperidinyl, morpholinyl or hexamethyleneiminoring;

R⁹ is cyano, CO₂R¹⁴, CONR¹⁴R¹⁴, CONR¹⁴SO₂R¹⁴, SO₂R¹⁴, heterocycle oroptionally substituted phenyl;

R¹⁰ and R¹¹ are independently at each occurrence H or C₁-C₆ alkyl;

R¹² is hydrogen, CO₂R¹⁵, CONR¹⁵R¹⁵, SO₂R¹⁵, SO₂NR¹⁶R¹⁶, optionallysubstituted phenyl or optionally substituted heterocycle,

R¹³ is cyano, NR¹⁶R¹⁶, NR¹⁶SO₂R¹⁶ or OR¹⁶;

R¹⁴, R¹⁵ and R¹⁶ are independently at each occurrence H, C₁-C₆ alkyl orphenyl; or when two R¹⁴ or two R¹⁵ or two R¹⁶ moieties are connected tothe same nitrogen atom, then said R¹⁴ or R¹⁵ or R¹⁶ moieties may combinewith the nitrogen to which they are attached to form a pyrollidinyl,piperidinyl, morpholinyl or hexamethyleneimino ring; or a pharmaceuticalsalt thereof.

The present invention also relates to processes for preparing, as wellas pharmaceutical formulations containing a compound of formula I. Inanother embodiment, the pharmaceutical formulations of the presentinvention may be adapted for use in treating Type 2 diabetes and obesityand for agonizing the β₃ receptor.

The present invention also relates to methods for treating Type 2diabetes and obesity, as well as a method for agonizing the β₃ receptoremploying a compound of formula I.

In addition, the present invention relates to a compound of formula Ifor use in treating Type 2 diabetes and obesity as well as a compound offormula I for use in agonizing the β₃ receptor. The present invention isfurther related to the use of a compound of formula I for themanufacture of a medicament for treating Type 2 diabetes and obesity asa well as for agonizing the β₃ receptor.

For the purposes of the present invention, as disclosed and claimedherein, the following terms are defined below.

The term “halo” represents fluoro, chloro, bromo, or iodo.

The term “C₁-C₆ alkyl” represents a straight, branched or cyclichydrocarbon moiety having from one to six carbon atoms, e.g., methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and thelike. The term “C₁-C₄ alkyl” refers specifically to methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyland cyclobutyl. A “C₁-C₄ haloalkyl” group is a C₁-C₄ alkyl moietysubstituted with up to six halo atoms, preferably one to three haloatoms. An example of a haloalkyl group is trifluoromethyl. A “C₁-C₆alkoxy” group is a C₁-C₆ alkyl moiety connected through an oxy linkage.

The term “C₃-C₇ carbocyclic ring” refers specifically to a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl ring.

The term “optionally substituted” as used herein means an optionalsubstitution of one to three, preferably one or two groups independentlyselected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C₁-C₆alkyl, C₁-C₄ haloalkyl, C₁-C₆ alkoxy, COR¹⁷, CONR¹⁷R¹⁷, CO₂R¹⁷, NR¹⁷R¹⁷,NR¹⁷COR¹⁸, NR¹⁷SO₂R¹⁸, OCOR¹⁸, OCO₂R¹⁷, OCONR¹⁷R¹⁷, SR¹⁷, SOR¹⁸, SO₂R¹⁸and SO₂(NR¹⁷R¹⁷), where R¹⁷ is independently at each occurrence H, C₁-C₆alkyl, phenyl or benzyl and R¹⁸ is independently at each occurrenceC₁-C₆ alkyl, phenyl or benzyl.

The terms “heterocycle” and “heterocyclic” represent a stable,saturated, partially unsaturated, fully unsaturated or aromatic 5 or 6membered ring, said ring having from one to four heteroatoms that areindependently selected from the group consisting of sulfur, oxygen, andnitrogen. The heterocycle may be attached at any point which affords astable structure. Representative heterocycles include 1,3-dioxolane,4,5-dihydrooxazole, furan, imidazole, imidazolidine, isothiazole,isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione,oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole,thiadiazole, thiazole, thiophene and triazole. Representative“benzofused” heterocycles include benzoxazole, benzimidazole,benzofuran, benzothiophene, benzothiazole, azaindole, and indole.Further specific examples of benzofused and non-benzofused heterocyclesare described below in the Preparations and Examples sections.

In the compound of formula I, the following moiety is found:

This moiety represents a 6,5 heteroaromatic fused bicyclic ring systemand is sometimes referred to herein as the “6,5 ring system”. The twocircles used in the structure of this moiety have been used to connotethat this bicyclic ring system is aromatic. The numbers on the perimeterof the pictured moiety represent the numbering system used in the claimsand preferred embodiments to describe positions of substituents off ofthe 6,5 ring system and/or connectivity onto said system.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “patient” includes human and non-human animals such ascompanion animals (dogs and cats and the like) and livestock animals.Livestock animals are animals raised for food production. Ruminants or“cud-chewing” animals such as cows, bulls, heifers, steers, sheep,buffalo, bison, goats and antelopes are examples of livestock. Otherexamples of livestock include pigs and avians (poultry) such aschickens, ducks, turkeys and geese. Yet other examples of livestockinclude fish, shellfish and crustaceans raised in aquaculture. Alsoincluded are exotic animals used in food production such as alligators,water buffalo and ratites (e.g., emu, rheas or ostriches).

The preferred patient of treatment is a human.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

The terms “preventing”, “prevention of”, “prophylaxis”, “prophylactic”and “prevent” are used herein interchangeably and refer to reducing thelikelihood that the recipient of a compound of formula I will incur ordevelop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” means an amount of acompound of formula I that is capable of treating conditions, ordetrimental effects thereof, described herein or that is capable ofagonizing the 13 receptor.

The term “selective β₃ receptor agonist” means a compound that displayspreferential agonism of the β₃ receptor over agonism of the β₁ or β₂receptor. Thus, 13 selective compounds behave as agonists for the β₃receptor at lower concentrations than that required for similar agonismat the β₁ and β₂ receptors. A β₃ selective compound also includescompounds that behave as agonists for the β₃ receptor and as antagonistsfor the β₁ and β₂ receptors.

The term “pharmaceutical” when used herein as an adjective meanssubstantially non-deleterious to the recipient patient.

The term “formulation”, as in pharmaceutical formulation, is intended toencompass a product comprising the active ingredient(s) (compound offormula I), and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical formulations of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutical carrier.

The term “unit dosage form” refers to physically discrete units suitableas unitary dosages for human subjects and other non-human animals (asdescribed above), each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

Because certain compounds of the invention contain an acidic moiety(e.g., carboxy), the compound of formula I may exist as a pharmaceuticalbase addition salt thereof. Such salts include those derived frominorganic bases such as ammonium and alkali and alkaline earth metalhydroxides, carbonates, bicarbonates, and the like, as well as saltsderived from basic organic amines such as aliphatic and aromatic amines,aliphatic diamines, hydroxy alkamines, and the like.

Because certain compounds of the invention contain a basic moiety (e.g.,amino), the compound of formula I can also exist as a pharmaceuticalacid addition salt. Such salts include the salicylate, sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate,chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hippurate, β-hydroxybutyrate, glycolate, maleate,tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and like salts. Preferred acidaddition salts include the hydrochloride and glycolate salts.

PREFERRED COMPOUNDS (EMBODIMENTS) OF THE INVENTION

Certain compounds of the invention are particularly interesting and arepreferred. The following listing sets out several groups of preferredcompounds. It will be understood that each of the listings may becombined with other listings to create additional groups of preferredcompounds.

-   a) m is 2;-   b) n is 0 or 1;-   c) n is 0;-   d) A¹, A² and A³ are carbon;-   e) the 6,5 ring system is of the formula:

-   f) the 6,5 ring system is of the formula:

-    where only one D can be nitrogen;-   g) the 6,5 ring system is of the formula:

-   h) the 6,5 ring system is 7-azaindole connected to the (CR⁴R⁵)_(n)    moiety at the 3-position of the azaindole ring system;-   i) the 6,5 ring system is 7-azaindole connected to the (CR⁴R⁵)_(n)    moiety at the 3-position of the azaindole ring system; n is 0; and    R⁷ is H;-   j) the 6,5 ring system is imidazo[1,5-a]pyridine and is connected to    the (CR⁴R⁵)_(n) moiety at the n imidazo[1,5-a]pyridine ring system;-   k) the 6,5 ring system is imidazo[1,2-a]pyridine and is connected to    the (CR⁴R⁵)_(n) moiety at the 3-position of the    imidazo[1,2-a]pyridine ring system;-   l) Het is at the ortho-position relative to X;-   m) Het is an optionally substituted 5-membered, non-benzofused ring    containing one or two heteroatoms that are independently selected    from the group consisting of sulfur, oxygen, and nitrogen;-   n) Het is selected from isoxazole; thiophene; and pyrrole; wherein    said Het moieties are optionally substituted once with chloro,    fluoro, cyano, methyl or COCH₃;-   o) Het is isoxazol-3-yl or thien-2-yl wherein said thien-2-yl moiety    is optionally substituted once with chloro, fluoro, cyano, methyl or    COCH₃;-   p) Het is isoxazol-3-yl or thien-2-yl wherein said thien-2-yl moiety    is optionally substituted once with COCH₃;-   q) Het is thien-2-yl;-   r) R¹ is H;-   s) R² is H;-   t) R³ is H;-   u) R⁴ and R⁵ are independently H or methyl at each occurrence;-   v) the moiety (CR⁴R⁵)_(m) is C(CH₃)₂CH₂;-   w) R⁶ is methyl at each occurrence;-   x) R⁷ is at the 6- or 7-position of the 6,5 ring system to which it    is attached;-   y) R⁷ is at the 7-position of the 6,5 ring system to which it is    attached-   z) R⁷ is H, O(CH₂)_(p)R¹² or optionally substituted heterocycle; p    is 0 or 1; and R¹² is CONR¹⁵R¹⁵, optionally substituted phenyl or    optionally substituted heterocycle;-   aa) R⁷ is H;-   bb) R⁷ is O(CH₂)_(p)R¹²; p is 0 or 1; and R¹² is CONR¹⁵R¹⁵, phenyl    or pyridyl substituted once with CONR¹⁷R¹⁷, where R¹⁷ is    independently at each occurrence H or C₁-C₆ alkyl;-   cc) R⁷ is thienyl;-   dd) X is OCH₂;-   ee) R¹⁵ and R¹⁷ are hydrogen at each occurrence;-   ff) the compound of formula I is an acid addition salt;-   gg) the compound of formula I is the hydrochloride salt.    Synthesis

The compound of formula I may be prepared as described in the followingSchemes and Examples.

The reaction of Scheme 1 may be carried out under conditions appreciatedin the art for the amination of epoxides. For example, the epoxide offormula II may be combined with an amine of formula III in a loweralcohol, dimethylformamide or dimethylsulfoxide, preferably ethanol,isopropanol, n-butanol or t-butanol, at room temperature to the refluxtemperature of the reaction mixture, preferably between 40° C.-90° C.The reaction may also be carried out tinder conditions generallydescribed in Atkins, et al., Tet. Let., 27:2451, 1986. These conditionsinclude mixing the reagents in the presence of trimethylsilyl acetamidein a polar aprotic solvent such as acetonitrile, dimethylformamide,acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether,tetrahydrofuran, or other polar aprotic solvents in which the reagentsare soluble.

The compound of formula I may also be prepared via a Suzuki couplingreaction as shown in Scheme 2.

A compound of formula IV may be reacted with a compound of formula IIIas described above in Scheme 1. The compound of formula V (an arylhalide) may then be reacted with a heteroaryl boronic acid, an arylboronic ester, or an aryl boronic cyclic ester, preferably an arylboronic acid, under conditions appreciated in the art for the couplingof aromatic halides with aryl boronic acids and their derivatives. Thiscoupling is known in the art generally as a Suzuki coupling. The skilledartisan will recognize that an aryl triflate may also be employed in thepresent Suzuki coupling as an alternative to employing an aryl halide.

The epoxide starting materials employed in Schemes 1 and 2 may beprepared by techniques recognized and appreciated by one skilled in theart. See, e.g., U.S. Pat. No. 4,663,334; European Patent Application171209; Korn, et al., J. Pharm. Sci., 69(9):1010-13, 1980; and PCTPatent Application No. PCT/US01/16519, filed Jul. 9, 2001 and referencescited below in the Preparations section for representative and/oranalogous procedures for preparing the epoxides of formula II and IV.

The amines of formula III employed in Scheme 1 may also be prepared bytechniques recognized and appreciated by one skilled in the art. See,e.g., the Preparations below or the references cited therein forrepresentative and/or analogous procedures for preparing the amines offormula III.

Compounds of the formula Het-B(OH)₂ are either commercially available,known in the art, or can be prepared by methods known in the art ordescribed herein.

Preparations

Epoxides of Formula II and IV

Epoxides 1-6 are prepared for use as described in Scheme 1. Theseepoxides are pictured below in Table 1.

TABLE 1

Het = 1

2

3

4

5

6

Epoxide 1

A mixture of 2-(thien-2-yl)phenol (J. Heterocycl. Chem., 22(6):1667-9,1985; 1 equivalent), (2S)-glycidyl 3-nitrobenzenesulfonate (1.2equivalents), potassium carbonate (1.2 equivalents) and acetone arerefluxed for 16 hours, cooled to room temperature and the solids removedvia filtration. The filtrate is concentrated and the crude productpurified on silica gel (ethyl acetate/hexane) to give the title epoxide.

Epoxides 2 and 3

2-(Pyrrol-1-yl)phenol (J. Het. Chem., 8:283-287, 1971) and2-(isoxazol-3-yl)phenol (J. Het. Chem., 8:283-287, 1971) are reactedwith (2S)-glycidyl 3-nitrobenzenesulfonate substantially as describedfor Epoxide 1 to yield the title epoxides.

Epoxide 4

2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g,17.6 mmol) in acetic anhydride (7.7 ml), and the mixture is allowed tostir overnight at ambient temperature. The mixture is refluxed for 5hours, concentrated, dissolved in 50 ml ethanol and stirred for 10 minwith 50 ml 2 M aqueous sodium hydroxide. After neutralisation withaqueous hydrochloric acid, and extraction with ethyl acetate, theorganic layer is dried and concentrated. The residue is purified bychromatography (toluene/ethanol 9:1) to yield2-(3-cyano-1-pyrrolyl)phenol (2.4 g, 92%). This phenolic product isreacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1 to yield the title epoxide.

Epoxide 5

A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol) in 50ml of dioxane is degassed with argon,tetrakis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) is addedand the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid(2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) aresuccessively added and the mixture is stirred for 16 hours at 85° C.Extractive work-up (2×50 ml dichloromethane and 2×30 ml water). Theorganic phase is dried over sodium sulfate, filtrated and evaporated.The residue (4.05 g) is purified via flash chromatography on silica(eluent: 100% hexane>hexane/ethyl acetate 96:4 gradient) to give 1.37 gof 2-(5-cyanothien-2-yl)anisole (96%). M+=215.

An intimate mixture of 2-(5-cyanothien-2-yl)anisole (1.2 g, 5.9 mmol)and pyridinium hydrochloride (13.7 g, 119 mmol) is heated for 1 hour at210° C. under argon. The mixture is cooled to ambient temperature and a1:1 mixture of water and ethyl acetate is added to break and dissolvethe solid cake formed during the reaction. The slurry is thentransferred to a separation funnel and dichloromethane is added untilthe organic phase had a higher density than the water phase (organicphase=lower phase). The organic phase contains the desired product andis separated. The remaining aqueous phase is additionally extractedtwice with dichloromethane and the collected organic phases are driedover sodium sulfate and evaporated. The residue is purified via flashcolumn on silica (eluent: 100% hexane>hexane/ethyl acetate 8:2 gradient)to give 973 mg of 2-(5-cyanothien-2-yl)phenol (87%). M+=201.

To a solution of 2-(5-cyanothien-2-yl)phenol (970 mg, 4.819 mmol) in 20ml of dry 2-butanone is added (2S)-glycidyl 3-nitrobenzenesulfonate(1.25 g, 4.82 mmol) and potassium carbonate (732 mg, 5.30 mmol)successively. After stirring for 48 hours at 75° C., the mixture isdiluted with ethyl acetate and extracted with 2N aqueous sodiumhydroxide (2×30 ml) and water (1×30 ml). (M+=257).

Epoxide 6

Epoxide 6 is prepared by a procedure substantially similar to thatdescribed for Epoxide 5. The starting halo thiophenes used to prepareEpoxides 5 and 6 are known from the literature, see e.g., J. Mater.Chem., 5(4), 653-61, 1995; J. Chem. Soc., Perkin Trans. 2, 5:625-30,1982; Chem. Scr., 5(5), 217-26, 1974; Bull. Soc. Chim. Fr., 11:4115-20,1967; Bull. Soc. Chim. Fr., 11:4121-6, 1967; Bull. Inst. Chem. Res.,52(3):561-5, 1974; J. Med. Chem., 43(16):3168-3185, 2000; Bioorg. Med.Chem. Lett., 10(5):415-418, 2000; and JP 08311060.

Epoxide 7

Epoxide 7 is prepared for use as described in Scheme 1. A mixture of2-iodophenol (5.00 g, 22.7 mmol),2,3-epoxypropyl-(2S)-3-nitrobenzenesulfonate (5.89 g, 22.7 mmol) andpotassium carbonate (3.44 g, 24.9 mmol) in methylethylketone (150 ml) isrefluxed for 18 hours. After cooling, the salts are removed byfiltration. The filter cake is rinsed thoroughly with dichloromethaneand the collected filtrates are evaporated. The residue is purified viaflash chromatography on silica gel using a hexane-hexane/ethyl acetategradient (100 to 90:10).

Amines of Formula III

Amines 1-25 are prepared or are obtained from commercial sources for useas described in Schemes 1 or 2. These amines are pictured below in Table2.

TABLE 2 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

19

20

21

22

23

24

25

Amine 1

A 0° C. solution of diacetonamine hydrogen oxalate (15 g, 73.1 mmol) in300 ml of CH₂Cl₂ and 35 ml of triethylamine is treated withtrifluoroacetic anhydride (10.3 ml, 73.1 mmol). The resulting mixture isallowed to warm to ambient temperature and stir overnight. Excess 1Naqueous HCl is added and the layers are separated. The aqueous layer isextracted with CH₂Cl₂ (150 ml), and the combined organic layers arewashed with a mixture of water and brine, dried over Na₂SO₄ andconcentrated in vacuo to an oil. Purification of the crude residue(SiO₂; linear gradient of 5 to 50% ethyl acetate in hexanes) affords 4.1g (19.4 mmol; 27%) of the trifluoroacetic acid amide.

A solution of the amide (4.0 g, 18.9 mmol) in 50 ml of methanol istreated with bromine (970 μl, 18.9 mmol) dropwise. The resulting mixtureis allowed to stir at ambient temperature overnight. The reactionmixture is concentrated in vacuo and partitioned between ethyl acetateand water. The organic layer is washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. Purification of the crude residue (SiO₂; lineargradient of 2 to 40% ethyl acetate in hexanes) affords 2.25 g (7.76mmol; 41%) of the desired α-bromoketone.

A solution of the α-bromoketone (900 mg, 3.1 mmol) and 2-aminopyridine(292 mg, 3.1 mmol) in 15 ml of ethanol is heated overnight at reflux.The reaction mixture is concentrated in vacuo. Purification of the crudeimidazopyridine (SiO₂; linear gradient of 0 to 5% 2M NH₃/methanol inCHCl₃) affords 616 mg (2.16 mmol; 70%) of the trifluoroacetic acid amideprotected title amine as a pale yellow waxy solid.

A slurry of the protected amine (570 mg, 2.0 mmol) and K₂CO₃ (1.4 g, 10mmol) in 20 ml of methanol and 6 ml of water is heated 2 days at 64° C.The reaction mixture is concentrated in vacuo and partitioned betweenCHCl₃ (20 ml) and water (10 ml). The aqueous layer is extracted withCHCl₃ (20 ml). The combined organic layers are dried over Na₂SO₄ andconcentrated in vacuo. Purification of the crude residue (SiO₂; lineargradient of 0 to 10% 2M NH₃/methanol in CHCl₃) affords 313 mg (1.65mmol; 83%) of the title amine.

Amine 2

2-(4-Bromo-3-oxo-butyl)-isoindole-1,3-dione is prepared by condensationof but-1-en-3-one with phthalimide followed by bromination according toknown procedures (J. Med. Chem., 35:3239, 1992. A solution of2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (8.9 g, 30.06 mmol) and2-aminopyridine (2.8 g, 29.75 mmol) in ethanol is heated at reflux for 4hours. The mixture is cooled to room temperature and concentrated. Theresidue is purified by chromatography (silica gel,dichloromethane/ethanol 95:5); to give 4.23 g of2-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione (49%).

A mixture of 2-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione(4.5 g, 15.45 mmol), 1,2-diaminoethane (25 ml), and isopropanol (125 ml)is heated at reflux at 125° C. for 5 hours. The solvent is removed underreduced pressure and the residue is treated with water (50 ml). Theaqueous wash is extracted with dichloromethane (3×50 ml). The combinedorganic layers are dried over magnesium sulfate and concentrated invacuo to leave 840 mg of the title amine (34%). (See also, J. Med.Chem., 16:1272, 1973.

Amine 3

A solution of 3,3 dimethylacrylic acid (30 g, 0.3 mol) in 360 ml of 28%aqueous ammonia is heated in an autoclave at 140° C. for 12 hours(internal pressure 15 bar). After cooling and pressure release, thereaction mixture is evaporated to a small volume and dissolved in 60 mlof ethanol. The solution is poured into 150 ml of ice coldtetrahydofuran. The colorless crystalline precipitate thus obtained iscollected by suction and dried at 50° C. for 4 hours in a vacuum oven togive 27.4 g of 3-amino-3-methyl butanoic acid (78%).

An intimate mixture of of 3-amino-3-methyl butanoic acid (27.4 g, 0.234mol) and phthalic anhydride (38.1 g, 0.257 mol) is heated at 180° C. for1.5 hours. After cooling, the reaction mixture is dissolved in 40 ml ofethanol and kept in a refrigerator for 54 hours. The colorlesscrystalline precipitate thus obtained is collected by suction and driedat 50° C. for 3 hours in a vacuum oven to give 19.2 g ofβ,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (58%).

To a solution of β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (5g, 20.2 mmol) and N,N-dicyclohexylcarbodiimide (4.6 g, 22.24 mmol) in 50ml of dry methylene chloride is added 2-(aminomethyl)pyridine (2.41 g,2.3 ml, 22.24 mmol) at ambient temperature. The mixture is stirred for24 hours. The precipitate of dicyclohexyl urea is filtered off anddiscarded. The filtrate is evaporated and the residue is purified viaflash chromatography on silica gel using a methylene chloride/methylenechloride-ethanolic ammonia gradient (100 to 96:4) to give 3.97 g ofN-[(2-pyridinyl)methyl]-1,3-dihydro-β,β-dimethyl-1,3-dioxo-2H-isoindole-2-propanamide(58%).

A solution ofN-[(2-pyridinyl)methyl]-1,3-dihydro-β,β-dimethyl-1,3-dioxo-2H-isoindole-2-propanamide(1.39 g, 4.12 mmol) in 30 ml of neat phosphoryl chloride is heated to75° C. for 19 hours. The reaction mixture is poured on crushed ice andextracted with methylene chloride. The organic phase is dried oversodium sulfate and evaporated. The residue is purified via flashchromatography on silica gel using a methylene chloride/methylenechloride-ethanolic ammonia gradient (100 to 96:4) to give 947 mg of2-(2-imidazo[1,5-a]pyridin-3-yl-2-methyl-propyl)-1H-isoindole-1,3(2H)-dione(72%).

To a solution of2-(2-imidazo[1,5-a]pyridin-3-yl-2-methyl-propyl)-1H-isoindole-1,3(2H)-dione(1.279 g, 3.98 mmol) in 17 ml of methanol is added hydrazine hydrate(1.39 g, 1.35 ml, 27.84 mmol) and the mixture heated to 100° C. for 15minutes in a microwave oven (MLS ETHOS 1600). The reaction mixture isevaporated. The residue is purified via flash chromatography on silicagel using a methylene chloride/methylene chloride-ethanolic ammoniagradient (100 to 96:4) to give 355 mg of the title amine (55%).

Amine 4

7-Azaindole (5.05 g, 43 mmol) and Eschenmoser's salt(N,N-dimethylmethyleneammonium iodide; 8.48 g, 45 mmol) are combined in100 ml of glacial acetic acid. After heating at 65° C. for 1 hour, thereaction mixture is concentrated in vacuo. The resulting solid istriturated with ethyl acetate, filtered and dried in vacuo to give3-dimethylaminomethyl-1H-7-azaindole hydroiodide in quantitative yield.

A 0° C. solution of 3-dimethylaminomethyl-1H-7-azaindole hydroiodide (10g, 33 mmol) in 46 ml of methanol and 46 ml of 2-nitropropane is treatedwith methyl iodide (2.15 ml, 35 mmol) and solid sodium methoxide (3.65g, 68 mmol) sequentially. The resulting mixture is allowed to warm toambient temperature, and, after stirring overnight, the reaction mixtureis diluted with ethyl acetate (100 ml) and saturated aqueous NH₄Clsolution (100 ml). The aqueous layer is extracted with ethyl acetate(2×100 ml), and the combined organic layers are dried over Na₂SO₄ andconcentrated in vacuo to give 3-(2-methyl-2-nitropropyl)-1H-7-azaindolein 92% yield.

A solution of 3-(2-methyl-2-nitropropyl)-1H-7-azaindole (2.3 g, 11 mmol)in 200 ml of tetrahydrofuran and 100 ml of ethyl acetate is treated withRaney nickel (2.0 g), and the resulting mixture is heated overnight (60°C.) under an atmosphere of H₂ (60 psi). The reaction mixture is filteredover celite and concentrated in vacuo. Purification of the crude residue(SiO₂; 10% 2M NH₃/methanol in CHCl₃) affords 1.0 g (50%) of the titleamine.

Amine 5

A 0° C. solution of 1,2-phenylenediamine (925 mg, 8.57 mmol) in 50 ml oftoluene is treated with Al(CH₃)₃ (2 M solution in toluene; 9.6 ml, 19.2mmol). After 30 minutes, 4-nitro-4-methylpentanoic acid methyl ester(1.0 g, 5.71 mmol) is added slowly. The resulting mixture is heated to95° C. and allowed to stir overnight at that temperature. The reactionmixture is cooled to ambient temperature, then quenched with water. Theresulting precipitate is filtered, rinsing well with methanol. Thefiltrate is concentrated in vacuo, and the crude residue is dissolved in50 ml of tetrahydrofuran and 50 ml of ethyl acetate, Raney nickel isadded, and the resulting mixture is heated overnight (60° C.) under anatmosphere of H₂ (60 psi). The reaction mixture is filtered over celiteand concentrated in vacuo. Purification of the crude residue (SiO₂;linear gradient of 0 to 15% 2M NH₃/methanol in CHCl₃) affords 515 mg(2.53 mmol; 30%) of the title amine.

Amine 6

A 0° C. solution of benzimidazole (3.0 g, 25.4 mmol) in 100 ml oftetrahydrofuran is treated with NaH (60% dispersion in mineral oil; 1.2g, 30.5 mmol). After 1 hour, (S)-(−)-propylene oxide (3.5 ml, 50.8 mmol)is added, and the resulting mixture is allowed to slowly warm to ambienttemperature and stir for 24 hours. The reaction mixture is quenched withH₂O and extracted with ethyl acetate. The organic layer is dried overNa₂SO₄ and concentrated in vacuo. Purification of the crude residue(SiO₂; ethyl acetate) affords 1.42 g (8.06 mmol; 32%) of the alkylatedproduct.

A 0° C. solution of the alkylated product (1.3 g, 7.38 mmol) in 40 ml ofCH₂Cl₂ and 3.1 ml of triethylamine is treated with methanesulfonylchloride (1.1 ml, 14.8 mmol). After 1.5 hours, the reaction mixture isdiluted with ethyl acetate (100 ml) and 1M aqueous Na₂CO₃ solution (100ml). The organic layer is washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude mesylate is dissolved in 40 ml ofdimethylformamide, and NaN₃ (960 mg, 14.8 mmol) is added. The resultingmixture is heated at 60° C. for 5 hours, then poured into H₂O (100 ml)and extracted with ethyl acetate (2×100 ml). The combined organic layersare washed with brine (100 ml), dried over Na₂SO₄ and concentrated is invacuo. The crude azide is dissolved in 25 ml of tetrahydrofuran andtreated with PPh₃ (2.56 g, 9.78 mmol). After stirring at roomtemperature overnight, the reaction mixture is treated with water (10ml) and heated at 60° C. for 6 hours to hydrolyze the intermediateaza-ylide. Upon cooling to ambient temperature, the reaction mixture isdiluted with ethyl acetate (200 ml) and brine (200 ml). The organiclayer is washed with brine (100 ml), dried over Na₂SO₄ and concentratedin vacuo. Purification of the crude residue by radial chromatography(SiO₂; 2.5% step gradient of 0% to 5% 2M NH₃/MeOH in CHCl₃) affords 527mg (3.01 mmol; 41%) of the title amine.

Amine 7

4-Methyl-4-nitropentanal is prepared by condensation of acrolein and2-nitropropane according to a known procedure (Synthesis 1986, 237). Toa solution of 4-methyl-4-nitropentanal (8.5 g, 58.56 mmol) in aceticacid (125 ml) is added bromine (9.12 g, 57.07 mmol) dropwise while thetemperature is kept below 15° C. After stirring for 15 minutes at roomtemperature the reaction is poured into a mixture of water and ice (250ml) and extracted two times with dichloromethane. The combined organicextracts are washed with water and with brine, successively, dried overmagnesium sulfate, and the solvent is removed under reduced pressure toleave 10.7 g of 2-bromo-4-methyl-4-nitropentanal which is used for thenext step without further purification.

A mixture of 2-amino-3-benzyloxypyridine (2.7 g, 13.5 mmol) and2-bromo-4-methyl-4-nitropentanal (3.0 g, 13.5 mmol) in ethanol (20 ml)is heated at 100° C. overnight. The solvent is removed under reducedpressure and the residue is treated with saturated aqueous NaHCO₃solution. The aqueous mixture is extracted two times with ethyl acetate.The combined organic extracts are dried over magnesium sulfate andconcentrated in vacuo. The residue is chromatographed (silica gel,dichloromethane/ethanol 9:1) to give 2.83 g of3-(2-methyl-2-nitropropyl)-8-(phenylmethoxy)imidazo[1,2-a]pyridine(64%).

Method A: To a solution of3-(2-methyl-2-nitropropyl)-8-(phenylmethoxy)imidazo[1,2-a]pyridine (1.1g, 3.38 mmol) in ethanol (20 ml) is added Raney-Ni (2 g). The mixture isset under an atmosphere of hydrogen and stirred vigorously overnight atroom temperature. The catalyst is removed by filtration through Celiteand the solvent is distilled off under reduced pressure to leave 850 mgof the title amine (85%).

Method B: A mixture of3-(2-methyl-2-nitropropyl)-8-(phenylmethoxy)imidazo[1,2-a]pyridine (0.46g, 1.41 mmol) and acetic acid (6 ml) is heated to 90° C. Powdered iron(0.8 g, 14.3 mmol) in water (3 ml) is added in three portions within 45minutes. After heating for another 2 hours at 90° C., the solids areremoved by filtration and washed with ethanol. The combined filtratesare concentrated under reduced pressure, and the residue is treated withsaturated aqueous NaHCO₃ solution (50 ml). The aqueous mixture isextracted with ethyl acetate (2×50 ml). The combined organic extractsare dried over magnesium sulfate, and the solvent is removed in vacuo.Chromatography (silica gel, dichloromethane/ethanol 9:1) of the residuegives 113 of the title amine (27%).

Amine 8

A solution of 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (4.1 g, 13.85mmol) and 2-amino-3-benzyloxypyridine (2.75 g, 13.73 mmol) in ethanol(20 ml) is heated at reflux for 4 hours. After one hour, the desiredcompound started to precipitate. The mixture is cooled to roomtemperature and the precipitate is collected by filtration, washed withethanol and hexane, successively, and dried in vacuo to give 5.43 g of2-[2-(8-phenylmethoxy-imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione(99%).

A mixture of2-[2-(8-phenylmethoxy-imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione(2.9 g, 7.3 mmol) and hydrazine hydrate (1.5 ml) in methanol (25 ml) isheated at reflux for 90 minutes. The formed precipitate is collected byfiltration and washed with ethanol. The filtrate is concentrated underreduced pressure to leave another crop of product which is heated with asmall amount of ethanol, filtered, and dried in vacuo to give a total of1.25 g of the title amine (64%).

Amine 9

2-Amino-4-hydroxypyridine is prepared according to a known procedure(Org. Proced. Prep. Int., 29: 117, 1997) and is reacted with2-bromo-4-methyl-4-nitropentanal (2.19 g, 19.9 mmol) as described forAmine 7. The reaction mixture is concentrated and the residue is treatedwith ethyl acetate (20 ml), heated and filtered to give 2.79 g of3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-ol (60%).

3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-ol (1.5 g, 6.38 mmol),chloroacetamide (1.19 g, 12.73 mmol), potassium carbonate (6.4 mmol) anda small amount of potassium iodide in 2-butanone (30 ml) is heated atreflux overnight. The solids are removed by filtration and the filtrateis concentrated under reduced pressure. The residue is chromatographedon silica gel with dichloromethane/methanol 3:1 to 1:1 to give 640 mg of2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-yloxy]-acetamide(34%).

The title compound is prepared (87%, 500 mg) from2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-yloxy]-acetamide(640 mg, 2.19 mmol) by the procedure described for Amine 7, Method A.

Amine 10

2-Amino-4-methylpyridine (2.2 g, 20.3 mmol) and2-bromo-4-methyl-4-nitropentanal (20.3 mmol) are reacted as described inAmine 7 to give 3.0 g of7-methyl-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (63%).

The title compound is prepared (96%, 2.5 g) from7-methyl-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (3.0 g, 12.9mmol) by the procedure described for Amine 7, Method A.

Amine 11

2-Amino-5-methoxypyridine (J. Med. Chem., 24:39, 1981; 2.02 g, 16.3mmol) and 2-bromo-4-methyl-4-nitropentanal (16.3 mmol) are reacted asdescribed in Amine 7 and the product is isolated in two crops from theconcentrated mixture by heating twice with dichloromethane (30 ml and 10ml) and filtration without further chromatographic purification to give1.71 g of 3-(2-methyl-2-nitropropyl)-6-methoxyimidazo[1,2-a]pyridine(42%).

The title compound is prepared from3-(2-methyl-2-nitropropyl)-6-methoxyimidazo[1,2-a]pyridine (1.68 g, 6.74mmol) by the procedure described for Amine 7, method A to give 1.27 g ofthe title amine (86%).

Amine 12

The trifluoroacetic acid amide protected intermediate is prepared fromcondensation of (2-amino-3-pyridinyloxy)acetonitrile (J. Gauthier, et alU.S. Pat. No. 4,492,697; J. Gauthier & J. S. Duceppe, J Hetcyc Chem,1984, 21(4), 1081-6) with the α-bromoketone described in the preparationof Amine 1 in 86% yield by essentially following the procedure describedfor the preparation of Amine 1. This product is deprotected andhydrolyzed with K₂CO₃ substantially as described for the preparation ofAmine 1 to give the title amine, which is used without chromatographicpurification, in 63% yield.

Amine 13

The title amine is prepared from 5-azaindole (M. J. Sloan & R. S.Phillips, Bioorg Med Chem Lett, 1992, 2(9), 1053-1056) by essentiallyfollowing the procedure described for Amine 4.

Amine 14

2-Amino-3-bromopyridine (J. Chem. Soc., Perkin Trans. I, 1999, 1505; 5.0g, 28.9 mmol) and 2-bromo-4-methyl-4-nitropentanal (28.9 mmol) arereacted as described in Amine 7 to prepare 5.09 g of8-bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (59%).

A mixture of 8-bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine(1.5 g, 5.0 mmol), Pd(PPh₃)₄ (0.68 g), 2M aqueous sodium carbonatesolution (8 ml), and dioxane (68 ml) is stirred for 30 minutes under anatmosphere of argon. After addition of thiophene-2-boronic acid (0.96 g,7.5 mmol), the mixture is stirred overnight at 80° C. The solids areremoved by filtration, and the residue is chromatographed (silica gel,dichloromethane/ethanol 95:5) to give 1.52 g of3-(2-methyl-2-nitropropyl)-8-(2-thienyl)imidazo[1,2-a]pyridine (100%).

The title compound is prepared (92%, 1.26 g) from3-(2-methyl-2-nitropropyl)-8-(2-thienyl)imidazo[1,2-a]pyridine (1.52 g,5.04 mmol) by the procedure described for Amine 7, Method A.

Amine 15

8-Bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.0 g, 3.35mmol) and 4-trifluoromethyl-benzeneboronic acid (0.96 g, 5.05 mmol) arecoupled as described in Amine 14 to give 1.23 g of3-(2-methyl-2-nitropropyl)-8-(4-trifluoromethyl-phenyl)imidazo[1,2-a]pyridine(100%).

The title compound is prepared (85%, 960 mg) from3-(2-methyl-2-nitropropyl)-8-(4-trifluoromethyl-phenyl)imidazo[1,2-a]pyridine(1.23 g, 3.38 mmol) by the procedure described for Amine 7, Method A.

Amine 16

8-Bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.0 g, 3.35mmol) and 2,4-(bistrifluoromethyl)benzeneboronic acid (1.3 g, 5.04 mmol)are coupled as described in Amine 14 to give 690 mg of8-(2,4-bis-trifluoromethyl-phenyl)-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine(48%).

The title compound is prepared (79%, 510 mg) from8-(2,4-bis-trifluoromethyl-phenyl)-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine(690 mg, 1.6 mmol) by the procedure described for Amine 7, Method A.

Amine 18

2-Amino-3-hydroxypyridine (1.1 g, 10.0 mmol) and2-bromo-4-methyl-4-nitropentanal (10.0 mmol) are reacted as described inAmine 7 to prepare 1.0 g of3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (42.5%).

3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.0 g, 4.25 mmol),tert-butyl chloroacetate (964 mg, 6.4 mmol), potassium carbonate (590mg, 4.27 mmol), and a small amount of potassium iodide in 2-butanone (30ml) are reacted as described in Amine 9. The crude product residue ischromatographed on silica gel with dichloromethane/ethanol 9:1 to give1.2 g of tert-butyl[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetate (81%).

The title compound is prepared (89%, 980 mg) from tert-butyl[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetate (1.2g, 3.43 mmol) by the procedure described for Amine 7, Method A.

Amine 19

A mixture of 3-hydroxy picolinic amide (10 g, 72 mmol), ethylbromoacetate (12.02 g, 72 mmol) and anhydrous potassium carbonate (10.9g, 79.2 mmol) in 250 ml of dry 2-butanone is heated at 80° C. for 20hours. After cooling, the inorganic salts are filtered off and thefiltrate is reduced to approximately 120 ml. After addition of coldt-butyl methyl ether the resulting precipitate is filtered off, rinsedwith cold t-butyl methyl ether and dried to give 8.6 g of3-(ethoxycarbonylmethoxy)picolinamide (53%).

To a solution of 3-(ethoxycarbonylmethoxy)picolinamide (5.1 g, 22.8mmol) and triethylamine (6.68 ml, 47.9 mmol) in 100 ml of dry methylenechloride is added trifluoroacetic anhydride (6.77 ml, 47.9 mmol),dropwise, at ambient temperature under argon. After stirring for 16hours, 100 ml of water is added. The organic phase is separated andwashed with aqueous sodium hydrogen carbonate to neutral pH. Afterdrying over sodium sulfate and evaporation, the residue is purified viaflash chromatography on silica gel using a methylene chloride-ethanolicammonia gradient (99:1 to 95:5) to give 3.90 g of2-cyano-3-(ethoxycarbonylmethoxy)pyridine (87%).

To a solution of 2-cyano-3-(ethoxycarbonylmethoxy)pyridine (3.2 g, 15.52mmol) in 180 ml of ethanol is added concentrated aqueous HCl (2.92 ml,35 mmol) and 10% palladium on charcoal (1.5 g). After stirring for 4hours under a hydrogen pressure of 4 bar, the mixture is filteredthrough celite, rinsed with ethanol and evaporated. The2-aminomethyl-3-(ethoxycarbonylmethoxy)pyridine dihydrochloride thusobtained is sufficiently pure and used in the next step without furtherpurification. Yield: 3.82 g (100%).

To a solution of 2-aminomethyl-3-(ethoxycarbonylmethoxy)pyridinedihydrochloride (610 mg, 2.155 mmol), triethylamine (732 μl, 5.258mmol), N,N-dicyclohexylcarbodiimide (596 mg, 2.892 mmol) and4-(N,N-diemethylamino)-pyridine (10 mg) in 6 ml of dry methylenechloride is added β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid(650 mg, 2.629 mmol) at ambient temperature. The mixture is stirred for24 hours. The precipitate of dicyclohexyl urea is filtered off. Thefiltrate is evaporated and the residue is purified via flashchromatography on silica gel using a methylene chloride/methylenechloride-ethanolic ammonia gradient (100 to 97:3) to give 591 mg of(2-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-butyrylamino]-methyl}-pyridin-3-yloxy)-aceticacid ethyl ester (46%).

A solution of(2-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-butyrylamino]-methyl}-pyridin-3-yloxy)-aceticacid ethyl ester (2.79 g, 6.349 mmol) in 100 ml of neat phosphorylchloride is stirred at 75° C. for 16 hours. The reaction mixture ispoured on 200 g of crushed ice and extracted with methylene chloride.The organic phase is dried over sodium sulfate and evaporated. Theresidue is purified via flash chromatography on silica gel using amethylene chloride/methylene chloride-ethanolic ammonia gradient (100 to96:4) to give 1.48 g of{3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-methyl-propyl]-imidazo[1,5-a]pyridin-8-yloxy}-aceticacid ethyl ester (55%).

To a solution of{3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-methyl-propyl]-imidazo[1,5-a]pyridin-8-yloxy}-aceticacid ethyl ester (1.48 g, 3.50 mmol) in 30 ml of ethanol is addedhydrazine hydrate (0.7 ml, 14 mMol) and the mixture is heated to 80° C.for 15 minutes in a microwave oven (MLS ETHOS 1600). The reactionmixture is evaporated. Flash chromatography of the residue on silica gelusing methylene chloride-ethanolic ammonia (80:20) yielded an equimolarmixture of the title amine and the corresponding 2-carbonyl hydrazidebenzamide. This mixture is further hydrolyzed with 5N HCl in isopropanolfor 16 hours at 70° C. The mixture is evaporated and the residue istreated with 5 ml of ethanolic ammonia. After repeated evaporation,flash chromatography on silica gel using a methylene chloride/methylenechloride-ethanolic ammonia gradient (100 to 90:10) gives 340 mg of thetitle amine (33%) slightly contaminated with traces of the correspondingi-propyl ester.

Amine 20

2-Aminopyridine (1.3 g, 13.8 mmol) and 2-bromo-4-methyl-4-nitropentanal(3.1 g, 13.8 mmol) are reacted as described in Amine 7 to prepare 2.59 gof 3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (85%).

The title compound is prepared (96%, 990 mg) from3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.2 g, 5.47 mmol) bythe procedure described for Amine 7, Method A.

Amine 21

8-Bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.0 g, 3.35mmol) and thiophene-3-boronic acid (0.64 g, 5.0 mmol) are coupled asdescribed in Amine 14 to give 760 mg of3-(2-methyl-2-nitropropyl)-8-(3-thienyl)imidazo[1,2-a]pyridine (75%).

The title compound is prepared from3-(2-methyl-2-nitropropyl)-8-(3-thienyl)imidazo[1,2-a]pyridine (760 mg,2.52 mmol) by the procedure described for Amine 7, method A to give 400mg of the title amine (58%).

Amine 22

The title amine is prepared from 5-azaindole (M. J. Sloan & R. S.Phillips, Bioorg Med Clem Lett, 1992, 2(9), 1053-1056) by essentiallyfollowing the procedure described for Amine 4.

Amine 23

3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.0 g, 4.25 mmol),chloroacetamide (598 mg, 6.4 mmol), potassium carbonate (885 mg, 6.4mmol), and a small amount of potassium iodide in butanone (30 ml) arereacted and the product, 115 mg of2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetamide,is purified as described in Amine 18 (9.3%).

The title compound is prepared (100%, 103 mg) from 2-[3-(2-methyl-2-2.5nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetamide (115 mg, 0.39 mmol)by the procedure described for Amine 7, Method A.

Amine 24

3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.0 g, 4.25 mmol),2-chloronicotinamide (1.0 g, 6.4 mmol), potassium carbonate (885 mg, 6.4mmol), and a small amount of potassium iodide in 2-butanone (30 ml) arereacted and the product, 490 mg of2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-pyridin-3-carboxamide,purified as described in Amine 18 (9.3%).

The title compound is prepared (100%, 450 mg) from2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-pyridin-3-carboxamide(490 mg, 1.38 mmol) by the procedure described for Amine 7, Method A.

Amine 25

The title compound is prepared (99%, 1.04 g) from3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.2 g, 5.10 mmol)by the procedure described for Amine 7, method A to give 1.04 g of thetitle amine (99%).

Boronic Acids

Boronic Acids 1 and 2 are obtained from commercial sources for use asdescribed in Scheme 2. These boronic acids are pictured below in Table3.

TABLE 3 1

2

Aryl Halides of Formula V

Aryl Halide 1

A solution of Epoxide 22 (496 mg, 1.69 mmol) and Amine 6 (410 mg, 1.69mmol) in dry ethanol (10 ml) is heated at 110° C. overnight. Afterevaporation of the solvent, the residue is purified via flashchromatography (silica gel, dichloromethane/ethanol 95:5 to 85:15) togive 150 mg of the title compound (17%). MS m/e=538.2 (M⁺+1).

EXAMPLES Representative Procedure 1: Amination of Epoxide

A vial is charged with a solution of single amine of formula III (0.2Min ethanol or t-butanol, 90 micromolar) and a solution of a singleepoxide of formula II (0.2M in dimethylsulfoxide, 80 micromolar). Thevial is sealed and heated to 80° C. for 24-48 hours. The solution iscooled to room temperature, diluted with methanol, and passed over acation exchange column, eluting the basic material with 1N methanolicammonia.

Representative Procedure 2: Amination of Epoxide

A stirred mixture of an epoxide of formula II (1 equivalent) and anamine of formula III (1-2 equivalents) in ethanol, methanol, n-butanolor t-butanol is heated at 70-80° C. for 2-72 hours. The solvent isevaporated to dryness to give a crude oil that is optionally dilutedwith methanol or ethanol and passed over a cation exchange column(eluting the free base product with 1N methanolic ammonia) beforefurther purification.

The final products prepared via Representative Procedure 1 or 2 may befurther purified by flash or radial chromatography. Typicalchromatography conditions include: a) using a variable mixture of 25:5:1chloroform/methanol/ammonium hydroxide and 9:1 chloroform/methanol; b) avariable mixture of 90:10:1 CH₂Cl₂/ethanolic NH₃ gradient; c)dichloromethane/6-12% methanol, 0.15-0.35M ammonia in dichloromethanegradient; d) methylene chloride with a step gradient to 2-8% methanol;e) chloroform/2.0M ammonia in methanol, from 0-10% to 5-20% gradientelution or f) isocratic 6-8% 2M ammonia in methanol: 92-94%dichloromethane.

Alternatively, the final products may be purified on C18 bonded silicagel using either mass guided or UV guided reverse phase liquidchromatography (acetonitrile/water with 0.01% hydrochloric acid or 0.1%trifluoroacetic acid). When purification of a compound of the presentinvention results in production of a free base, the free base thusprepared may be salified, e.g., by dissolution of the free base inCH₂Cl₂ or diethylether, adding 1M ethanolic HCl or a solution of HCl indiethylether, and evaporating the volatiles, or as described in moredetail below.

For example, a hydrochloride salt may be prepared by dissolving the freebase in dichloromethane, diethylether, or a mixture of ethyl acetate andmethanol and adding 1M ethanolic HCl, a solution of HCl in diethylether,or 0.5M ammonium chloride in methanol. The resulting mixture is allowedto stir for a short time, e.g., for five minutes, before evaporating thevolatiles and optionally triturating in diethyl ether to give thehydrochloride salt.

The oxalate salts may be prepared by dissolving the free base in a smallamount of ethyl acetate, optionally adding methanol for solubitity. Theresulting solution is treated with 1 equivalent of a 0.5M solution ofoxalic acid in ethyl acetate. The reaction mixture is eitherconcentrated in vacuo or centrifuged, separated, and the solids aredried, to give the oxalate salt.

To prepare a succinate salt, the free base may be dissolved in a smallamount of ethyl acetate or methanol and then treated with 1 equivalentof succinic acid in methanol. The resulting slurry is dissolved in theminimum amount of methanol then concentrated in vacuo to give thesuccinate salt.

The table below sets out representative combinations of Amines andEpoxides that are reacted as described in Representative Procedure 1 or2. Preparation of desired product is confirmed via mass spectralanalysis (MSA). Emax±Standard Error Mean (SEM) data, discussed in the“Demonstration of Function” section below, is also included for saidcompounds where available. The Emax values represent the average of atleast 3 runs except as otherwise indicated.

TABLE 3 E.g. Epoxide Amine MSA Isolated Form Emax (%) ± SEM 1 1 1 422.2Hydrochloride 50.8 ± 0.4 2 1 3 422.2 Hydrochloride 58.6 ± 3.4 3 1 4422.2 Hydrochloride 66.9 ± 2.1 4 1 5 436.2 Hydrochloride 50.2 ± 2.3 5 16 408.2 Hydrochloride 42.2 ± 2.5 6 1 7 528.2 Hydrochloride 67.8 ± 3.9 71 9 495.4 Trifluoroacetate 37.4 ± 5.9 8 1 10 436.2 Hydrochloride 90.6 ±4.4 9 1 11 452.2 Free Base 66.7 ± 3.7 10 1 12 496.2 Hydrochloride 73.3 ±2.0 11 1 13 422.2 Hydrochloride 59.0 ± 6.2 12 1 14 504.0 Hydrochloride62.2 ± 7.5 13 1 15 566.2 Hydrochloride 53.1 ± 1.8 14 1 16 634.0Hydrochloride 80.0 ± 5.7 15 1 20 422.2 Hydrochloride 51.2 ± 4.0 16 1 21504.2 Hydrochloride 63.0 ± 0.7 17 1 22 422.2 Hydrochloride 59.9 ± 0.8 181 23 495.4 Hydrochloride 70.9 ± 1.0 19 1 24 557.8 Hydrochloride 88.4 ±3.0 20 2 3 405.2 Hydrochloride 42.7 ± 2.8 21 2 10 419.2 Hydrochloride62.1 ± 1.4 22 2 11 435.2 Trifluoroacetate 37.1 ± 1.7 23 3 1 407.2Hydrochloride 36.7 ± 1.6 24 3 2 379.4 Trifluoroacetate 10.0 ± 0.0 25 3 3430.0 Hydrochloride 53.7 ± 1.9 26 3 4 407.2 Hydrochloride 65.6 ± 1.8 273 8 485.3 Hydrochloride 18.3 ± 3.3 28 3 10 421.2 Hydrochloride 61.6 ±0.3 29 3 12 481.2 Hydrochloride 51.0 ± 4.4 30 3 14 489.2Trifluoroacetate 64.4 ± 5.8 31 3 15 551.4 Hydrochloride 45.2 ± 1.0 32 316 619.4 Hydrochloride 68.0 ± 5.1 33 3 20 407.4 Hydrochloride 42.9 ± 2.034 3 21 489.2 Hydrochloride 43.4 ± 2.0 35 3 24 543.2 Hydrochloride 68.9± 4.7 36 3 25 423.2 Hydrochloride 46.8 ± 5.5 37 4 3 407.2 Hydrochloride25.4 ± 5.0 38 5 3 447.0 Hydrochloride 67.5 ± 4.3 39 6 3 436.0Hydrochloride 62.9 ± 3.3 40 5 19 549.2 Hydrochloride 76.5 ± 2.6

Example 41

A vial is charged with a solution of Amine 19 (0.2M in t-butanol, 300micromolar) and a solution of Epoxide 1 (0.2M in dimethylsulfoxide, 300micromolar). The vial is sealed and heated to 80° C. for 16 hours. Thesolution is cooled to room temperature, and passed over a cationexchange column, removing the impurities by eluting with methanol, andeluting the product with 1N methanolic ammonia. Under thesechromatography conditions the product ester is hydrolyzed (about 66%) tothe corresponding acid. Further purification of the mixture is achievedby flash chromatography on silica gel using a methylenechloride/ethanolic ammonia gradient (100 to 95/5. The desired fractionsare evaporated, dissolved in a small volume of methylene chloride andtreated with excess 1N ethanolic HCl. After evaporation of the volatilesthe hydrochlorides of the title compounds are obtained. MSA 495.2/524.2.

Example 42

Amine 19 and Epoxide 4 are reacted as described above for Example 42 toprepare a mixture of the title compounds. MSA 503.2/532.2.

Example 43

A vial is charged with a solution of Amine 18 (319 mg, 1 mmol) andEpoxide 3 (217 mg, 1 mmol) in 5 ml of ethanol. The vial is sealed andheated to 85° C. for 16 hours. The solution is cooled to roomtemperature and concentrated under reduced pressure. Purification of themixture is achieved by HPLC on a Hyperprep column C-18 using awater/acetonitrile gradient (9:1 up to 100% acetonitrile) containing0.1% trifluoroacetic acid. The desired fractions are evaporated,dissolved in a small volume of dichloromethane and treated with excess1N ethanolic HCl. After evaporation of the volatiles the title compoundis obtained; MSA 481.2; yield: 39.3 mg (7.6%).

Representative Procedure 3: Suzuki Coupling

Procedure 3(a)

A compound of formula V (6.4 mmol) is dissolved in 50 ml of dry dioxaneand thoroughly flushed with argon. Palladium(0)tetrakis(triphenylphosphine) (750 mg, 0.64 mmol) is added under argonand stirred at ambient temperature until the mixture becomes homogenous.The clear solution is divided into aliquots of 2 ml, and each testingtube is charged with 2 equivalents of an aryl boronic acid and 500microliters of 2M aqueous sodium carbonate under argon. The testingtubes are sealed and heated in a microwave oven (MLS ETHOS 1600) for 35minutes and 100° C. at 1000 W. After complete conversion the samples arediluted with 2 ml of water and extracted with 3 ml of dichloromethane.Extraction is repeated with 2 ml of dichloromethane. The organicsolutions are collected and dried over sodium sulfate. The organicfiltrate is treated with pre-treated Amberlyst 15 (3 to 4 g each).(Prior to use Amberlyst 15 is prewashed with dichloromethane, ethanolthen dichloromethane until the filtrate is colorless). The suspensionsare shaken for 30 minutes on an orbital shaker and filtered. TheAmberlyst is repeatedly rinsed with dichloromethane/ethanol 1:1 (4×3 ml)and then repeatedly treated with dichloromethane/ethanolic ammonia 1:1.Finally the resin is treated with ethanolic ammonia overnight. Thealkaline filtrates are collected and evaporated.

Procedure 3(b)

A mixture of an aryl halide of formula V (1.2 mmol), a boronic acid (2.4mmol), palladium(0) tetrakis(triphenylphosphine) (0.06 mmol), and 2Maqueous sodium carbonate (1.5 ml) in dioxane (20 ml) is heated overnightat 100° C. in a sealed tube. The mixture is poured into water andextracted two times with ethyl acetate. The combined organic layers arewashed with brine, dried over sodium sulfate, and concentrated underreduced pressure.

The final products prepared via Suzuki coupling may be purified bynormal phase chromatography (silica gel, dichloromethane/ethanolicammonia) providing the free bases or by reverse phase chromatography(acetonitrile/0.1% trifluoroacetic acid or 0.01% HCl in water) providingthe trifluoroacetate or hydrochloride salts. The final products existingas salts may also be prepared in a separate salification step bydissolution of the free base in ethanol or dichloromethane and treatmentof the solution with acid, e.g., 1N ethanolic HCl. Removal of allvolatiles under reduced pressure, affords the desired salt.

The table below sets out representative combinations of aryl halides andboronic acids that are reacted as described above in RepresentativeProcedure 3(a) or 3(b).

TABLE 4 Aryl Boronic E.g. Halide Acid MSA Isolated Form Emax (%) ± SEM44 1 1 422.2 Hydrochloride 44.5 ± 4.1 45 1 2 464.3 Free Base 63.5 ± 2.4Demonstration of Function

The genes encoding the human β₁-adrenergic receptor (Frielle et al.,Proc. Natl. Acad. Sci., 84:7920-7924, 1987), the human β₂-adrenergicreceptor (Kobika et al., Proc. Natl. Acad. Sci., 84:46-50, 1987, Emorineet al., Proc. Natl. Acad. Sci., 84:6995-6999, 1987) and the human 133adrenergic receptor (Granneman et al., Molecular Pharmacology,44(2):264-70, 1993) are individually subcloned into a phd expressionvector (Grinnell et al., Bio/Technology, 5:1189-1192, 1987) andtransfected into the DXB-11 Chinese hamster ovary (CHO) cell line bycalcium phosphate precipitation methodology. The stably transfectedcells are grown to 95% confluency in 95% Dulbecco's modified EaglesMedium (DMEM), 5% fetal bovine serum and 0.01% proline. Media is removedand the cells are washed with phosphate buffered (pH 7.4) saline(without magnesium and calcium). Cells are then lifted using an enzymefree cell dissociation solution (Specialty Media, Lavallette, N.J.) andpelleted by centrifugation.

Cells from each of the above cell lines are resuspended and added(20,000/well) to a 96-well plate. Cells are incubated at 37° C. withrepresentative compounds of the invention for 20 minutes in buffer(Hank's balanced salt solution, 10 mM HEPES, 0.1% BSA, 1 mM L-ascorbicacid, 0.2% dimethyl sulfoxide, 1 nm 3-isobutyl-1-methylxanthine, pH7.4). After halting the incubation with quench buffer (50 mM Na Acetate,0.25% Triton X-100, pH 5.8), the c-AMP level is quantified byscintillation proximity assay (SPA) using a modification of thecommercially available c-AMP kit (Amersham, Arlington Heights, Ill.)with rabbit anti-cAMP antibody (ICN Biomedicals, Aurora, Ohio) for thekit.

Sigmoidal dose response curves, from the whole cell receptor coupledc-AMP assay are fit to a four parameter logistic equation using nonlinear regression: y=(a−d)/(1+(Dose/c)^(b))+d where a and d areresponses at zero and maximal dose, b is the slope factor and c is theEC₅₀ as previously described (DeLean et al., Am. J. Physiol., 235,E97-E102, 1978). EC₅₀ is assessed as the concentration producing 50% ofthe maximum response to each agonist.

Isoproterenol is accepted in the art as a non-selective β₃ agonist andis widely used as a comparator in evaluating the activity of compounds.See Trends in Pharm. Sci., 15:3, 1994. The % intrinsic activity (Emax)of representative compounds of the invention is assessed relative toisoproterenol by the compound's maximal response divided by theisoproterenol maximal response times 100.

In Vitro Rat Atrial Tachycardia

Male rats (250-350 g) (Harlan Sprague Dawley, Indianapolis, Ind., USA)are killed by cervical dislocation. Hearts are removed and the left andright atria are dissected and mounted with thread in tissue bathscontaining 10 mls of modified Krebs' solution. Initial resting tensionis 1.5-2.0 g at the outset of the experiment (Naunyn-Schmied Arch.Pharmacol., 320:145, 1982). Tissues are allowed to equilibrateapproximately 30 minutes with vigorous oxygenation before exposure to acompound of the invention.

To evaluate the ability of test compounds to increase heart rate,representative compounds of the present invention are added cumulativelyonce the atrial rate reaches a steady state from the previous addition.Compound addition is continued until no further increase in atrial rateoccurs or until a concentration of 10⁻⁴M is reached. The increase inbeats per minute (bpm) is measured for each concentration of testcompound by means of a BioPac System (Br. J. of Pharmacol.,126:1018-1024, 1999).

Utilities

As agonists of the β₃ receptor, a compound of the present invention isuseful in treating conditions in human and non-human animals in whichthe β₃ receptor has been demonstrated to play a role.

The diseases, disorders or conditions for which compounds of the presentinvention are useful in treating or preventing include, but are notlimited to, (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4)hyperlipidemia, (5) hypertriglyceridemia, (6) hypercholesterolemia, (7)atherosclerosis of coronary, cerebrovascular and peripheral arteries,(8) gastrointestinal disorders including peptid ulcer, esophagitis,gastritis and duodenitis, (including that induced by H. pylori),intestinal ulcerations (including inflammatory bowel disease, ulcerativecolitis, Crohn's disease and proctitis) and gastrointestinalulcerations, (9) neurogenic inflammation of airways, including cough,asthma, (10) depression, (11) prostate diseases such as benign prostatehyperplasia, (12) irritable bowel syndrome and other disorders needingdecreased gut motility, (13) diabetic retinopathy, (14) neuropathicbladder dysfunction, (15) elevated intraocular pressure and glaucoma and(16) non-specific diarrhea dumping syndrome.

Human patients in need of obesity treatment are typically those with abody mass index (BMI)≧27 or those with a BMI≧25 when co-morbidities,e.g., hypertension, sleep apnea and/or osteoarthritis, are present. Apatient population at particular need of treatment are those with aBMI>30 or >27 with co-morbities.

Human patients in need of hypertension treatment are frequentlyoverweight individuals, i.e., those with a BMI≧5, but may also be ofnormal body weight (i.e., BMI<25).

Human patients in need of type 2 diabetes treatment are typicallyindividuals with a BMI<25, i.e., individuals that are not overweight.

Formulation

The compound of formula I is preferably formulated in a unit dosage formprior to administration. Therefore, yet another embodiment of thepresent invention is a pharmaceutical formulation comprising a compoundof formula I and a pharmaceutical carrier.

The present pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (formula Icompound) will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a capsule,sachet, paper or other container. When the carrier serves as a diluent,it may be a solid, semisolid or liquid material which acts as a vehicle,excipient or medium for the active ingredient. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (asa solid or in a liquid medium), soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

FORMULATION EXAMPLES Formulation 1

Tablets Ingredient Quantity (mg/tablet) Active Ingredient  5-500Cellulose, microcrystalline 200-650  Silicon dioxide, fumed 10-650Stearate acid 5-15The components are blended and compressed to form tablets.

Formulation 2

Suspensions Ingredient Quantity (mg/5 ml) Active Ingredient 5-500 mgSodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution0.10 ml Flavor q.v. Color q.v. Purified water to 5 mlThe medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

Formulation 3

Intravenous Solution Ingredient Quantity Active Ingredient   25 mgIsotonic saline 1,000 mlThe solution of the above ingredients is intravenously administered to apatient at a rate of about 1 ml per minute.Dose

The specific dose administered is determined by the particularcircumstances surrounding each situation. These circumstances include,the route of administration, the prior medical history of the recipient,the pathological condition or symptom being treated, the severity of thecondition/symptom being treated, and the age and sex of the recipient.However, it will be understood that the therapeutic dosage administeredwill be determined by the physician in the light of the relevantcircumstances.

Generally, an effective minimum daily dose of a compound of formula I isabout 5, 10, 15, or 20 mg. Typically, an effective maximum dose is about500, 100, 60, 50, or 40 mg. Most typically, the dose ranges between 15mg and 60 mg. The exact dose may be determined, in accordance with thestandard practice in the medical arts of “dose titrating” the recipient;that is, initially administering a low dose of the compound, andgradually increasing the dose until the desired therapeutic effect isobserved.

Route of Administration

The compounds can be administered by a variety of routes including theoral, rectal, transdermal, subcutaneous, topical, intravenous,intramuscular or intranasal routes.

Combination Therapy

A compound of formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of formula I are useful,e.g., treatment of obesity and/or type 2 diabetes. Such other drug(s)may be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of formula I. When acompound of formula I is used contemporaneously with one or more otherdrugs, a pharmaceutical unit dosage form containing such other drugs inaddition to the compound of formula I is preferred. Accordingly, thepharmaceutical compositions of the present invention include those thatalso contain one or more other active ingredients, in addition to acompound of formula I.

1. A compound of the formula:

wherein: m is 2; n is 0 or 1; A¹, A² and A³ are carbon; Het is at theortho-position relative to X and is isoxazol-3-yl; R¹, R² and R³ are H;R⁴ and R⁵ are independently H or methyl at each occurrence; the 6,5 ringsystem is connected to the (CR⁴R⁵)₂ moiety at the 2 or 3-position of the6,5 ring system; R⁶ is independently at each occurrence hydroxyl ormethyl; R⁷ is at the 6- or 7-position of the 6,5 ring system to which itis attached and is selected from H, O(CH₂)_(p)R¹² or thienyl; X is OCH₂;p is 0 or 1; and R¹² is CO₂R¹⁵, CONH₂, phenyl optionally substitutedwith one or two —CF₃ groups or pyridyl substituted once with CONH₂ whereR¹⁵ is H or C₁-C₆ alkyl; or a pharmaceutical salt thereof.
 2. A compoundwhich is:

or a pharmaceutical salt thereof.
 3. The compound of claim 1 which isthe hydrochloride salt.
 4. A pharmaceutical formulation comprising acompound of claim 1 and a pharmaceutical carrier.
 5. A method oftreating Type 2 Diabetes comprising administering to a patient in needthereof an effective amount of a compound of claim
 1. 6. A method oftreating obesity comprising administering to a patient in need thereofan effective amount of a compound of claim 1.